US5047464A - Bioerodible thermoset elastomers - Google Patents
Bioerodible thermoset elastomers Download PDFInfo
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- US5047464A US5047464A US07/409,908 US40990889A US5047464A US 5047464 A US5047464 A US 5047464A US 40990889 A US40990889 A US 40990889A US 5047464 A US5047464 A US 5047464A
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- poly
- hydroxy
- hydroxy terminated
- thermoset
- elastomer
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
- C08G65/34—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from hydroxy compounds or their metallic derivatives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/2031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
- A61K9/204—Polyesters, e.g. poly(lactide-co-glycolide)
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
Abstract
Bioerodible, thermoset, covalently crosslinked, elastomeric poly(ortho ester)s are disclosed. These materials are comprised of polymer chains that are interlocked in a covalent, three dimensional network which imparts dimensional stability. Use of these thermoset, covalently crosslinked materials as a drug delivery device is also disclosed.
Description
The reaction of diketene acetals with alcohols to produce poly (ortho ester)s was disclosed in U.S. Pat. No. 4,304,767. Known bioerodible poly(ortho ester)s, such as those described in U.S. Pat. No. 4,549,010, are comprised of linear polymer chains joined to one another by non-covalent intermolecular forces such as Van der Waal's dispersive forces and hydrogen bonding. These poly(ortho- ester)s are thermoplastic, i.e., their individual polymer chains slip by one another ("flow") if subjected to stress. This results in an irreversible deformation of the elastomers and accounts for their lack of resiliency when subjected to prolonged stress. Such characteristics are particularly disadvantageous in applications such as a gastric retention platform wherein the polymers, after having been subjected to stress during prolonged storage, are expected to behave in a resilient fashion.
A gastric retention platform, as disclosed in U.S. Pat. Nos. 4,735,804 and 4,758,436, is a drug delivery device comprised of a resilient polymer combined with an active ingredient. The platform is maintained in a first compressed state from the time of manufacture until ingestion. Subsequent to ingestion, the platform expands to a second relaxed state, thereby releasing the active ingredient to an environment of use (such as the stomach). The prolonged stress and strain suffered during storage limits the resilience of linear, thermoplastic polymer platforms and impedes their ability to expand to the second relaxed state subsequent to ingestion.
Covalently cross-linked poly(ortho ester)s are disclosed which exhibit greatly improved resiliency subsequent to prolonged periods of stress and strain as compared to previously known poly(ortho ester)s. The materials of the instant invention are thermoset, i.e., polymer chain slip is minimized under stress because the polymers are interlocked in a covalent, three-dimensional network. These thermoset, covalently cross-linked poly(ortho ester)s are synthesized by reacting either monomeric or polymeric polyols with diketene acetals.
It is a significant feature of this invention that monomeric polyols with a functionality of at least three, and/or polymeric polyols having a hydroxy functionality of at least two, must be used to produce the resilient, thermoset, covalently cross-linked bioerodible poly(ortho ester)s. Such monomeric or polymeric polyols do not exhibit resilient or elastic characteristics before reaction with diketene acetals. Rather, we have discovered that resiliency or elasticity is a latent property of those polyols that only becomes expressed upon reaction with diketene acetals to form the polymer. These polymers are suitable as carriers or matrices for drugs and other beneficial agents. Upon contact with an aqueous environment of use, the polymer degrades to release the drug or beneficial agent. The polymer may also constitute a structural member of a device requiring elasticity, resilience, and erodibility features.
FIG. 1: illustrates the general reaction scheme used in making the thermoset, elastomeric poly (ortho ester)s of the instant invention.
FIG. 2: is the stress/strain curve for the polymer samples of Example 1.
FIG. 3: is the stress/strain curve for polymer samples of Example 2.
FIG. 4: illustrates a controlled release device manufactured in accordance with the instant invention.
Polymeric polyols which can be reacted with diketene acetals to form the thermoset, covalently linked poly(ortho ester)s of the present invention include:
Poly(butadiene) hydroxy terminated (PBD);
Poly(isobutylene) hydroxy terminated (PIBD);
Poly(isoprene) hydroxy terminated (PIPD);
Poly(dimethylsiloxane) hydroxy terminated (PDMSD);
Poly(butadiene-co-styrene) hydroxy terminated;
Poly(ethylene-co-propylene) hydroxy terminated; and
Poly(chloroprene) hydroxy terminated.
These polymeric polyols must have hydroxy functionality (number of hydroxyl groups per molecule) of at least two to effect polymerization with functionality greater than two effecting cross-linking. The above list is illustrative and is not meant to be limiting.
Monomeric polyols which may be admixed with the polymeric polyols and then reacted with diketene acetals to form the polymers claimed herein can be represented generally by the formula: ##STR1## wherein R is a linear or branched hydrocarbon chain of 3 to 12 carbon atoms and y is 0 to 3. Typical monomeric polyols include: 1, 2, 6-hexanetriol; 2-ethyl-2-(hydroxymethyl)-1,3-propanediol; 1,5,10-decanetriol; and pentaerythritol; and the like.
A generalized reaction scheme for synthesizing the elastomers of the present invention is disclosed in FIG. 1.
A representative list of acceptable diketene acetals which will react with the aforementioned polyols to form our resilient, thermoset polymers is disclosed in U.S. Pat. Nos. 4,304,767 and 4,903,709, the complete disclosures of which are hereby incorporated by reference.
Our elastomers can also be modified by adding appropriate fillers, plasticizers and stabilizers (e.g., antioxidants) such as those described in the "Encyclopedia of Polymer Science and Technology", Fillers, Vol. 6, p. 740; Plasticizers, Vol. 10, p. 286; Antioxidants and Stabilizers, Vol. 2, pg 171. (John Wiley & Sons, Inc., New York).
Fillers serve as reinforcing agents and processing aids and can include: silicates such as clay, talc, feldspar, calcium silicate, and magnesium silicate; oxides such as aluminum oxide, titanium dioxide, zinc oxide, magnesium oxide, silica, quartz, and diatomaceous earth; carbonates such as calcium carbonate, barium carbonate and magnesium carbonate; sulfates such as barium sulfate and calcium sulfate; carbons such as carbon black and; polymeric fibers such as KEVLAR® aramid pulp (KEVLAR® is a registered trademark of the Dupont Corporation).
Plasticizers can also be added to the elastomers of the present invention, e.g., to lower the glass transition temperature, Tg. Such plasticizers include plasticizing oils such as SUNDEX® 170 (SUNDEX® is a registered Trademark of the Sun Oil Co.); phthalic esters; citrate esters; phosphate esters; adipic esters; azelaic esters; stearic esters; and complex linear polyesters and polymeric plasticizers.
Antioxidants retard oxidation and extend the polymer's useful life. They include diarylamines, substituted phenols, disubstituted cresols, bisphenols, derivatives of cathecol, benzoates and ketone-amine resins. Specific examples include butylated hydroxyanisole, butylated hydroxytoluene, propyl gallate and t-butyl hydroquinone.
The bioerodible thermoset elastomers of the present invention can be used as structural components of drug delivery devices and as tissue prostheses. They are also useful in the manufacture of matrices or other controlled release devices into which, or onto which, beneficial agents are included for subsequent use as implants or controlled release oral formulations.
One application of our thermoset polymers is in the manufacture of gastric retention devices such as those described in U.S. Pat. Nos. 4,735,804 and 4,758,436. In one form, the retention device is compressed within a gelatin capsule which dissolves in the stomach subsequent to ingestion. Upon dissolution of the capsule, the compressed retention device expands due to elastic forces to a size or shape that prevents it from exiting the stomach. The acidic environment of the stomach eventually degrades the device permitting exit from the stomach. Our thermoset, covalently cross-linked elastomers are uniquely suited to this application because they are bioerodible and because they retain their resiliency after compression for extended periods of time.
Our bioerodible, thermoset, covalently cross-linked elastomers may also serve as matrices for the controlled release of drugs. A drug may be associated with the matrix in different ways, depending on the physical and chemical properties of the drug. For example, the drug may be dispersed as a solution or suspension within the erodible elastomeric polymer matrix. As the matrix erodes within the gastrointestinal tract or implant site, the drug is released at a controlled rate.
The amount of drug or beneficial substance incorporated into the polymer matrix will vary greatly depending on the particular drug, the desired therapeutic effect and the time span over which the polymer matrix is eroded to release the particular drug. Thus, there is no critical upper limit to the amount of drug incorporated into the erodible elastomeric polymer matrix. In general, the amount of polymer employed in the practice of the invention will usually range from about 10% to 99% by weight of the device. The remaining portion of the composition contains the drug, and other excipients and additives.
When exposed to simulated gastric fluid (pH 1.25) the example elastomers hydrolytically degrade to regenerate the polyols, pentaerythritol dipropionate, and pentaerythritol.
FIGS. 2 and 3 show the elongation of elastomeric samples # 1 and #2 as a function of force/unit area (Instron™ data). The absence of yield-upon-elongation indicates good resilience. Polymers that yield with elongation will not recover the initial configuration (poor resilience) and are considered poor elastomers. While other properties (tensile or otherwise) can be used to characterize elastomeric nature, the property of reversible elongation or reversible deformation is a desirable characteristic of an elastomeric polymer. FIGS. 2 and 3 show that sample # 1 is stronger (harder) than sample # 2.
The invention is further illustrated by the following examples.
141.8 g PBD (approximate molecular weight 4,900; hydroxyl number 46.6 mg KOH/g polymer) was poured into a reaction kettle. To this was added HT (7.44 g) and 177 mg of butylated hydroxytoluene (BHT; antioxidant). The mixture was heated to 90° C. and vigorously stirred for 30 minutes with an overhead stirrer to effect mixing. While stirring continuously, the mixture was allowed to cool to room temperature (approximately 20° C.), then DETOSU (28.9 g) was added via syringe. Stirring was continued for 5 minutes. The resulting viscous polymer was removed from the reaction kettle, molded between steel plates lined with Teflon™ under pressure to form sheets, and cured at 60° C. for 12 hours. The elastomer thus obtained was labelled sample # 1. The tensile properties of sample # 1 analyzed with an INSTRON™ instrument. The properties of the final poly(ortho ester) are determined by the nature of the reactant polyols and diketene acetal(s) and by the stoichiometry (S) and crosslinker content (wt % crosslinker) of the reaction mixture where
S=(ketene acetal equivalents)/(hydroxyl equivalents)
and the weight percent of crosslinker is: ##EQU1##
The crosslink density of the synthesized polymer is directly proportional to the weight percent of crosslinker and to the functionality (the hydroxyl number) of the polymeric polyol used. The synthesis of the elastomers is depicted in the generalized overall reaction scheme of FIG. 1 where the R of the generalized diketene acetal structure represents a quadrivalent grouping that is part of a spiro or a non-spiro structure. The tensile behavior (Instron test) of our polymer samples is shown in FIG. 2 and the summarized properties are listed in Table 1.
TABLE 1 ______________________________________ TENSILE PROPERTIES.sup.a OF POLY(ORTHO ESTER) ELASTOMERS HT Tensile Tough- Break Sample (% Modulus strength ness strain (n = 5) S.sup.b w/w) (psi) (psi) (psi) (%) ______________________________________ #1 1.0 5 91.9 ± 79.1 ± 68.2 ± 143.4 ± 5.8 10.9 25.5 29.7 #2 1.0 0 30.5 ± 35.2 ± 115.5 ± 502.5 ± 2.3 4.1 16.3 5.0 ______________________________________ .sup.a The data was obtained with an INSTRON .sup.® using an ASTM D63 typeIV die (elastomeric) with a 50 Kg load cell with flat faced serrated grips (distance betweengrips 3 inches); crosshead speed = 2 inch/min; gauge length = 1.3 inches. S.sup.b = Stoichiometry.
The procedure of Example 1 was followed except that HT was omitted. The elastomer synthesized was labelled sample # 2. The tensile properties of sample # 2 were analyzed and are illustrated in FIG. 3 and summarized in Table 1.
DETOSU is reacted with PBD, PIBD, PIPD, or PDMSD, in the presence of varying amounts of crosslinker (0 to 50% w/w) in the manner described in Examples 1 and 2. The elastomers thus synthesized are used to fabricate the tetrahedral device of FIG. 4. The open tetrahedron measures 2×2×2 cm and when compressed fits into a No. 000 gelatin capsule. A biologically active compound may be incorporated into the elastomer.
PBD (82.2 g), HT (35.4 g), BHT (190 mg), MgO (195 mg) were mixed in a Helicone™ (Atlantic Res. Co., Gainesville, Va.) mixer at 60° C. for 1 hour under vacuum (to degas components). Magnesium oxide served to retard the polymerization rate (upon the addition of DETOSU) thereby allowing an adequate mixing time and avoiding premature curing (scorching) inside the mixer. After cooling the mixture to 40° C., the vacuum was released and DETOSU (72.66 g) was added. Mixing was continued (without vacuum) for 20 minutes. The extent of the reaction was monitored by analyzing the viscosity of the mixture every 5 minutes. The viscous polymer was transferred from the mixer into a Teflon™-lined mold and cured into a sheet at 60° C. for 18 hours.
The procedure of Example 4 was followed except that the stoichiometry (S) was equal to 1. This was accomplished by increasing the DETOSU level to 90.82 g.
The procedure of Example 4 was followed except that the stoichiometry (S) was equal to 1.2. This was accomplished by increasing the DETOSU level to 108.98 g.
Claims (6)
1. A bioerodible, thermoset, covalently cross-linked poly(ortho ester) elastomer synthesized by the reaction of a diketene acetal with (i) a polymeric polyol having a hydroxy functionality of at least two and (ii) 0-50% by weight of monomeric polyol, based on the total weight of (i) and (ii), having a hydroxy functionality of at least three.
2. The elastomer of claim 1 wherein the polymeric polyol is selected from the group consisting of
poly(butadiene) hydroxy terminated;
poly(isobutylene) hydroxy terminated;
poly(isoprene) hydroxy terminated;
poly(dimethylsiloxane) hydroxy terminated;
poly(butadiene-costyrene) hydroxy terminated;
poly(ethylene-copropylene) hydroxy terminated;
poly(chloroprene) hydroxy terminated.
3. The elastomer of claim 1, wherein the monomeric polyol is selected from the group consisting of 1, 2, 6 hexanetriol; 2-ethyl-2-(hydroxymethyl)-1,3-propanediol; 1, 5, 10-decanetriol; and pentaerythritol.
4. The elastomers of claim 3, wherein the diketene acetal is 3, 9-bis(ethylidene 2,4,8,10-tetraoxaspiro [5.5] undecane).
5. An elastomeric device comprising:
a thermoset, covalently cross-linked poly(ortho ester) matrix synthesized by the reaction of a diketene acetal with (i) a polymeric polyol having a hydroxy functionality of at least two and (ii) 0 to 50% by weight of monomeric polyol, based on the total weight of (i) and (ii), having a hydroxy functionality of at least three;
said matrix being resiliently transformable from a compressed state to an expanded state.
6. The elastomer of claim 1, further comprising at least one of the following: a filler, a plasticizer and a stabilizer.
Priority Applications (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US07/409,908 US5047464A (en) | 1989-09-20 | 1989-09-20 | Bioerodible thermoset elastomers |
CA002025480A CA2025480A1 (en) | 1989-09-20 | 1990-09-17 | Bioerodible thermoset elastomers |
EP19900310107 EP0419156A3 (en) | 1989-09-20 | 1990-09-17 | Bioerodible thermoset elastomers |
JP2247625A JPH03128934A (en) | 1989-09-20 | 1990-09-19 | Biodegradable thermosetting elastomer |
US07/715,951 US5217712A (en) | 1989-09-20 | 1991-06-17 | Bioerodible thermoset elastomers |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US07/409,908 US5047464A (en) | 1989-09-20 | 1989-09-20 | Bioerodible thermoset elastomers |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
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US07/715,951 Division US5217712A (en) | 1989-09-20 | 1991-06-17 | Bioerodible thermoset elastomers |
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Publication Number | Publication Date |
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US5047464A true US5047464A (en) | 1991-09-10 |
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Application Number | Title | Priority Date | Filing Date |
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US07/409,908 Expired - Fee Related US5047464A (en) | 1989-09-20 | 1989-09-20 | Bioerodible thermoset elastomers |
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Country | Link |
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US (1) | US5047464A (en) |
EP (1) | EP0419156A3 (en) |
JP (1) | JPH03128934A (en) |
CA (1) | CA2025480A1 (en) |
Cited By (14)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5211951A (en) * | 1991-07-24 | 1993-05-18 | Merck & Co., Inc. | Process for the manufacture of bioerodible poly (orthoester)s and polyacetals |
US5556905A (en) * | 1994-03-30 | 1996-09-17 | Reilly Industries, Inc. | Physically-modified degradable thermoplastic compositions |
US20030105245A1 (en) * | 2001-05-07 | 2003-06-05 | Amsden Brian G. | Biodegradable elastomer and method of preparing same |
US20030130472A1 (en) * | 2001-05-11 | 2003-07-10 | Ap Pharma, Inc. | Bioerodible poly (orthoesters)from dioxolane-based diketene acetals |
US20030152630A1 (en) * | 2001-05-11 | 2003-08-14 | Ng Steven Y. | PEG-POE, PEG-POE-PEG, and POE-PEG-POE block copolymers |
US6685962B2 (en) | 1999-11-29 | 2004-02-03 | Yissum Research Development Company Of The Hebrew University Of Jerusalem | Gastroretentive controlled release pharmaceutical dosage forms |
US6946145B2 (en) | 2001-11-16 | 2005-09-20 | A.P. Pharma, Inc. | Block copolymers based on poly(ortho esters) containing amine groups |
US7220414B2 (en) | 2000-09-06 | 2007-05-22 | A.P. Pharma, Inc. | Degradable polyacetal polymers |
WO2015191920A1 (en) * | 2014-06-11 | 2015-12-17 | Massachusetts Institute Of Technology | Residence structures and related methods |
US9421178B2 (en) | 2011-12-02 | 2016-08-23 | Synchroneuron, Inc. | Acamprosate formulations, methods of using the same, and combinations comprising the same |
US10166207B2 (en) | 2013-06-05 | 2019-01-01 | Synchroneuron, Inc. | Acamprosate formulations, methods of using the same, and combinations comprising the same |
US10596110B2 (en) | 2014-06-11 | 2020-03-24 | Massachusetts Institute Of Technology | Residence structures and related methods |
US11576866B2 (en) | 2016-09-30 | 2023-02-14 | Lyndra Therapeutics, Inc. | Gastric residence systems for sustained delivery of adamantane-class drugs |
US11576859B2 (en) | 2015-10-23 | 2023-02-14 | Lyndra Therapeutics, Inc. | Gastric residence systems for sustained release of therapeutic agents and methods of use thereof |
Families Citing this family (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5254345A (en) * | 1991-10-11 | 1993-10-19 | Merck & Co., Inc. | Poly(orthocarbonate acetal) bioerodible polymers |
US5968543A (en) * | 1996-01-05 | 1999-10-19 | Advanced Polymer Systems, Inc. | Polymers with controlled physical state and bioerodibility |
BR9706960A (en) * | 1996-01-05 | 1999-12-28 | Advanced Polymer Systems Inc | Controlled polymers with physical state and bioerosion condition |
US6280745B1 (en) | 1997-12-23 | 2001-08-28 | Alliance Pharmaceutical Corp. | Methods and compositions for the delivery of pharmaceutical agents and/or the prevention of adhesions |
US7045589B2 (en) | 2002-11-15 | 2006-05-16 | A.P. Pharma, Inc. | Bioerodible poly(ortho esters) from dioxane-based di(ketene acetals), and block copolymers containing them |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4304767A (en) * | 1980-05-15 | 1981-12-08 | Sri International | Polymers of di- (and higher functionality) ketene acetals and polyols |
US4549010A (en) * | 1984-06-27 | 1985-10-22 | Merck & Co., Inc. | Bioerodible poly(ortho ester) thermoplastic elastomer from diketene diacetal |
US4735804A (en) * | 1985-05-10 | 1988-04-05 | Merck & Co., Inc. | Drug delivery device which can be retained in the stomach for a controlled period of time |
US4758436A (en) * | 1985-05-29 | 1988-07-19 | Merck & Co., Inc. | Drug delivery device which can be retained in the stomach for a controlled period of time |
-
1989
- 1989-09-20 US US07/409,908 patent/US5047464A/en not_active Expired - Fee Related
-
1990
- 1990-09-17 EP EP19900310107 patent/EP0419156A3/en not_active Withdrawn
- 1990-09-17 CA CA002025480A patent/CA2025480A1/en not_active Abandoned
- 1990-09-19 JP JP2247625A patent/JPH03128934A/en active Pending
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4304767A (en) * | 1980-05-15 | 1981-12-08 | Sri International | Polymers of di- (and higher functionality) ketene acetals and polyols |
US4549010A (en) * | 1984-06-27 | 1985-10-22 | Merck & Co., Inc. | Bioerodible poly(ortho ester) thermoplastic elastomer from diketene diacetal |
US4735804A (en) * | 1985-05-10 | 1988-04-05 | Merck & Co., Inc. | Drug delivery device which can be retained in the stomach for a controlled period of time |
US4758436A (en) * | 1985-05-29 | 1988-07-19 | Merck & Co., Inc. | Drug delivery device which can be retained in the stomach for a controlled period of time |
Cited By (30)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5211951A (en) * | 1991-07-24 | 1993-05-18 | Merck & Co., Inc. | Process for the manufacture of bioerodible poly (orthoester)s and polyacetals |
US5556905A (en) * | 1994-03-30 | 1996-09-17 | Reilly Industries, Inc. | Physically-modified degradable thermoplastic compositions |
US6685962B2 (en) | 1999-11-29 | 2004-02-03 | Yissum Research Development Company Of The Hebrew University Of Jerusalem | Gastroretentive controlled release pharmaceutical dosage forms |
US7220414B2 (en) | 2000-09-06 | 2007-05-22 | A.P. Pharma, Inc. | Degradable polyacetal polymers |
US6984393B2 (en) | 2001-05-07 | 2006-01-10 | Queen's University At Kingston | Biodegradable elastomer and method of preparing same |
US20030105245A1 (en) * | 2001-05-07 | 2003-06-05 | Amsden Brian G. | Biodegradable elastomer and method of preparing same |
US20030130472A1 (en) * | 2001-05-11 | 2003-07-10 | Ap Pharma, Inc. | Bioerodible poly (orthoesters)from dioxolane-based diketene acetals |
US6822000B2 (en) | 2001-05-11 | 2004-11-23 | Ap Pharma, Inc. | Bioerodible poly (orthoesters) from dioxolane-based diketene acetals |
US20030152630A1 (en) * | 2001-05-11 | 2003-08-14 | Ng Steven Y. | PEG-POE, PEG-POE-PEG, and POE-PEG-POE block copolymers |
US6946145B2 (en) | 2001-11-16 | 2005-09-20 | A.P. Pharma, Inc. | Block copolymers based on poly(ortho esters) containing amine groups |
US10512621B2 (en) | 2011-12-02 | 2019-12-24 | Synchroneuron, Inc. | Methods of treating posttraumatic stress disorder with acamprosate salts |
US9421178B2 (en) | 2011-12-02 | 2016-08-23 | Synchroneuron, Inc. | Acamprosate formulations, methods of using the same, and combinations comprising the same |
US9421179B2 (en) | 2011-12-02 | 2016-08-23 | Synchroneuron, Inc. | Acamprosate formulations, methods of using the same, and combinations comprising the same |
US9427420B2 (en) | 2011-12-02 | 2016-08-30 | Synchroneuron, Inc. | Acamprosate formulations, methods of using the same, and combinations comprising the same |
US10166207B2 (en) | 2013-06-05 | 2019-01-01 | Synchroneuron, Inc. | Acamprosate formulations, methods of using the same, and combinations comprising the same |
US10610482B2 (en) | 2014-06-11 | 2020-04-07 | Massachusetts Institute Of Technology | Residence structures and related methods |
US10716751B2 (en) | 2014-06-11 | 2020-07-21 | Massachusetts Institute Of Technology | Residence structures and related methods |
US10517819B2 (en) | 2014-06-11 | 2019-12-31 | Massachusetts Institute Of Technology | Residence structures and related methods |
US10517820B2 (en) | 2014-06-11 | 2019-12-31 | Massachusetts Institute Of Technology | Residence structures and related methods |
US10532027B2 (en) | 2014-06-11 | 2020-01-14 | Massachusetts Institute Of Technology | Residence structures and related methods |
US10596110B2 (en) | 2014-06-11 | 2020-03-24 | Massachusetts Institute Of Technology | Residence structures and related methods |
WO2015191920A1 (en) * | 2014-06-11 | 2015-12-17 | Massachusetts Institute Of Technology | Residence structures and related methods |
US10716752B2 (en) | 2014-06-11 | 2020-07-21 | Massachusetts Institute Of Technology | Residence structures and related methods |
US10182985B2 (en) | 2014-06-11 | 2019-01-22 | Massachusetts Institute Of Technology | Residence structures and related methods |
US11246829B2 (en) | 2014-06-11 | 2022-02-15 | Massachusetts Institute Of Technology | Residence structures and related methods |
RU2766335C2 (en) * | 2014-06-11 | 2022-03-15 | Массачусетс Инститьют Оф Текнолоджи | Retained structures and related methods |
US11357723B2 (en) | 2014-06-11 | 2022-06-14 | Massachusetts Institute Of Technology | Residence structures and related methods |
US11389399B2 (en) | 2014-06-11 | 2022-07-19 | Massachusetts Institute Of Technology | Residence structures and related methods |
US11576859B2 (en) | 2015-10-23 | 2023-02-14 | Lyndra Therapeutics, Inc. | Gastric residence systems for sustained release of therapeutic agents and methods of use thereof |
US11576866B2 (en) | 2016-09-30 | 2023-02-14 | Lyndra Therapeutics, Inc. | Gastric residence systems for sustained delivery of adamantane-class drugs |
Also Published As
Publication number | Publication date |
---|---|
EP0419156A3 (en) | 1991-10-16 |
CA2025480A1 (en) | 1991-03-21 |
JPH03128934A (en) | 1991-05-31 |
EP0419156A2 (en) | 1991-03-27 |
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